Abstract
Purpose
YM543 is a novel selective inhibitor of the sodium-glucose cotransporter 2. The objectives of the current study were to evaluate the utility of mice with humanized livers to predict human drug metabolites using YM543 as a case example.
Methods
Metabolites of YM543 generated in humans and experimental animals including chimeric mice with humanized liver, PXB mice, were analyzed via liquid chromatography-mass spectrometry, liquid chromatography-radiometric detector or nuclear magnetic resonance spectrometer.
Results
After oral administration of YM543, metabolites M1–M5 were detected in human plasma and urine. M2–M4 were detected in at least one species while M1 was not generated by experimental animals or in vitro systems. In the metabolite profiling in PXB mice, M1 was detected in both plasma and urine samples.
Conclusions
Metabolite profile of YM543 in PXB mice and humans was closely resemble. and the human specific metabolite was detected in the model mice. The human specific metabolite, M1, was difficult to know in advance to clinical study. The ability to predict the human metabolite profile including presence of human specific metabolites using PXB mice will likely facilitate development of new drug candidates for human use.
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Abbreviations
- COSY:
-
Correlation spectroscopy
- CYP:
-
Cytochrome P450
- HMBC:
-
Heteronuclear multiple bond correlation
- HPLC:
-
High-performance liquid chromatography
- HSQC:
-
Heteronuclear single quantum coherence
- i.d:
-
Internal diameter
- LC:
-
Liquid chromatography
- MPLC:
-
Medium pressure liquid chromatography
- MS:
-
Mass spectrometry or mass spectrometer
- NMR:
-
Nuclear magnetic resonance spectroscopy or nuclear magnetic resonance spectrometer
- NOESY:
-
Nuclear Overhauser effect spectroscopy
- RAD:
-
Radiometric detector
- ROESY:
-
Rotating frame Overhauser effect spectroscopy
- SGLT2:
-
Sodium-glucose cotransporter 2
- TOCSY:
-
Total correlation spectroscopy
- UV:
-
Ultraviolet
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ACKNOWLEDGMENTS AND DISCLOSURES
The author thanks Mr. Aiji Miyashita, Mr. Kinya Soda, Ms Masami Watanabe, Dr. Fumihiko Ushigome, Mr. Katsuhiro Suzuki, Dr. Yasuhisa Nagasaka, Mr. Kinya Souda, Dr. Mitsuhiro Sekiguchi, Dr. Kazuyoshi Nozaki, Dr. Akio Kawamura, Dr. Takafumi Iwatsubo, Dr. Takashi Usui and Dr. Hidetaka Kamimura (Astellas Pharma Inc.) and Mr. Yoshihiko Haino (Kotobuki Pharmaceutical) for their useful advice.
Naoyuki Nakada is an employee Astellas Pharma Inc. No funding has been received for the conduct of this study.
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Nakada, N. Evaluation of the Utility of Chimeric Mice with Humanized Livers for the Characterization and Profiling of the Metabolites of a Selective Inhibitor (YM543) of the Sodium-Glucose Cotransporter 2. Pharm Res 34, 874–886 (2017). https://doi.org/10.1007/s11095-017-2116-4
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DOI: https://doi.org/10.1007/s11095-017-2116-4